The Midwest Sickle Cell Center (MSCC) is built upon the longstanding scientific relationship that exists between the multi-disciplinary research sickle cell disease (SCD) teams at the Medical College of Wisconsin and Washington University School of Medicine. The MSCC unites basic research, translational research, clinical outcomes analyses, and excellent comprehensive clinical services to improve the understanding and management of complications of SCD. Inter-Center Project 1 will test the safety and efficacy of the addition of intravenous magnesium to standard therapy for acute vaso-occlusive events in a double-blind, randomized, placebo-controlled trial. While the primary outcomes are safety and length of hospital stay, this Project will also investigate the effect of magnesium therapy on the nitric oxide pathway and endothelial dysfunction, synergizing with Projects 4 and 5. Patient Outcomes Project 3 will develop a pediatric- and SCD-specific health-related quality of life module that will be a critical tool to measure the impact of SCD and effect of treatment from the perspective of the patient. Basic Project 4 will study the role of hemolysis in the altered vascular responses found in human and murine SCD by examining the interplay between nitric oxide, lipid oxidation and cell free hemoglobin. Translational Project 5 will examine the role of cysteinyl leukotrienes and chronic inflammation in the development of SCD pathologies. The basic science component will explore biological mechanisms in both human and murine SCD using the cysteinyl leukotriene receptor inhibitor, montelukast. The clinical portion of Project 5 will conduct a safety trial to assure that montelukast does not increase morbidity (pain) and a feasibility trial to determine if montelukast has the potential to reduce the systemic measures of the inflammatory response. Administrative Core A will provide scientific, fiscal and administrative support for the MSCC. In additional to providing rigorous sate-of-the-art comprehensive care for children and adults with SCD, Clinical Core B will serve as the clinical research infrastructure for human subjects research within all three intra-Center Projects and the planned collaborative inter-Center trials. Patient Services Core C will focus on educational services for patients, families and communities impacted by SCD. Finally, Animal Core D will provide essential services and expertise for the in vivo studies using murine models in Projects 4 and 5. Relevance to Public Health: The MSCC is dedicated to providing state-of-the-art comprehensive clinical care to individuals with SCD, as well as to promoting cutting edge clinical, translational and basic research that leads us to a better understanding of the severe pathologies associated with SCD and promotes education and quality of life. Thus, the MSCC is well poised to achieve the high quality clinical care and SCD-specific research goals of a national Comprehensive Sickle Cell Center program.